Host cell Z-RNAs activate ZBP1 during virus infections

Journal article

Herpes simplex virus 1 (HSV-1) and influenza A viruses (IAV) induce Z-form-nucleic-acid-binding protein 1 (ZBP1)-initiated cell death1, 2, 3, 4, 5, 6, 7–8. ZBP1 is activated by Z-RNA1, 7, 9, and the Z-RNAs that trigger ZBP1 during HSV-1 and IAV infections were assumed to be of viral origin1. Here, however, we show that host cell-encoded Z-RNAs are major and sufficient ZBP1-activating ligands after infection by these two human pathogens. The majority of cellular Z-RNAs mapped to intergenic endogenous retroelements embedded within abnormally long 3′ extensions of host cell mRNAs. These aberrant host cell transcripts arose as a consequence of disruption of transcription termination (DoTT)—a virus-driven phenomenon that disables cleavage and polyadenylation specificity factor (CPSF)-mediated 3′ processing of nascent pre-mRNAs10, 11, 12, 13, 14–15. Mutant viruses lacking ICP27 or NS1—the virus-encoded proteins responsible for inhibiting CPSF and triggering DoTT13, 15—did not induce host cell Z-RNA accrual and were attenuated in their ability to stimulate ZBP1. Ectopic expression of HSV-1 ICP27 or IAV NS1 or pharmacological blockade of CPSF activity induced accumulation of host cell Z-RNAs and activated ZBP1. These results demonstrate that DoTT-generated cellular Z-RNAs are bona fide ZBP1 ligands, and position ZBP1-activated cell death as a host response to counter viral disruption of the cellular transcriptional machinery.

Authors: Yin, C; Fedorov, A; Guo, H; Crawford, JC; Rousseau, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature
• Volume: 648
• Issue: 8094
• Pages: 707-716
• Publication date: 2025-10-13
• Acceptance date: 2025-10-03
• DOI: 10.1038/s41586-025-09705-5
• EISSN: 1476-4687
• ISSN: 0028-0836
• Language: English